The long-term objective of this project is to contribute to our understanding of the mechanisms by which bladder cancers are induced so that factors which may be useful for interrupting the carcinogenic process can be identified. The present proposal is focused on the metabolic events that may contribute to the difference of susceptibilities of human slow and rapid acetylator phenotypes and of various species to bladder carcinogenesis by arylamines that are associated with human bladder cancer. It is hypothesized that the difference in susceptibility may be due to variations in urothelial and hepatic enzymes. This hypothesis is to be tested by examining N-acetyltransferase, N-deacetylase and UDP-glucuronosyltransferase activity in the liver. Activation enzymes such as N,O-acetyltransferase, O-acetyltransferase, N-deacetylase, and prostaglandin H synthase will be examined in urothelium of slow and rapid acetylator phenotypes. The presence of activation enzymes in the urothelium of dogs and rats will also be examined. Urothelial cells of these three species will be used to compare induction of unscheduled DNA synthesis (UDS) and enzyme-catalyzed binding to tRNA by arylamine metabolites. Since the N-glucuronides of arylhydroxylamines have been suspected to be the major urinary metabolites responsible for bladder carcinogenesis, the metabolism of the N-glucuronide of N-OH-AF in the rat will be investigated. The proposed experiments will contribute to the understanding of hepatic factors that may affect the carcinogenicity of arylamines and to the identification of reactions that may cause the initiation of carcinogenesis by urinary arylamine metabolites.